The incidence of adenocarcinoma of the gastroesophageal (GE) junction has risen dramatically over the last three decades. Outcomes continue to be poor with 5 year survivals estimated at 15%. These poor outcomes are related to the advanced presentation in the majority of patients in addition to the resistance esophageal adenocarcinoma displays to cisplatin based chemotherapy or radiation especially when each is administered alone. Only one-third of patients will have significant benefit and achieve complete responses when treated with the combination of cisplatin-based chemotherapy and radiation followed by surgical resection. Therefore, the need persists for overcoming resistance to cisplatin-based chemotherapy and radiation. Previous studies have highlighted the role of DNA repair pathways in resistance to cisplatin or radiation in a number of solid organ malignancies. The nucleotide repair pathway (NER) repairs the majority of cisplatin-induced DNA lesions while DNA double-strand breaks (DSBs) formed in response to radiation are repaired by homologous recombination (HR) and the non-homologous end-joining (NHEJ) pathways. We hypothesized that cisplatin and radiation resistance in esophageal adenocarcinoma is mediated through abnormalities in these DNA repair pathways. Using paired GE junction adenocarcinoma tumor samples with their matched normal tissue, we analyzed the expression of DNA repair genes in NER, HR and NHEJ pathways using quantitative RT-PCR. We identified overexpression of genes involved in HR in esophageal tumor samples in comparison to their normal counterparts. Eme1, an endonuclease present in complex with Mus81, showed consistent overexpression in GE junction adenocarcinoma samples. Mus81-Eme1 has been shown to play an important role in rescuing stalled replication forks and has been implicated in the repair of interstrand crosslinks, such as those formed in response to cisplatin therapy. Eme1 overexpression in esophageal adenocarcinoma could play a role in resistance to cisplatin through its impact on the repair of cisplatin induced DNA lesions. In addition, Eme1 overexpression could lead to genomic instability contributing to pathogenesis, metastases and therapeutic resistance. Further understanding the implications of Eme1 overexpression in these processes in GE junction adenocarcinoma will be of significant value.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3099. doi:1538-7445.AM2012-3099